CN102850327A - Intermediate for preparing Dabigatran etexilate, and preparation method and application thereof - Google Patents
Intermediate for preparing Dabigatran etexilate, and preparation method and application thereof Download PDFInfo
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- CN102850327A CN102850327A CN2012102039971A CN201210203997A CN102850327A CN 102850327 A CN102850327 A CN 102850327A CN 2012102039971 A CN2012102039971 A CN 2012102039971A CN 201210203997 A CN201210203997 A CN 201210203997A CN 102850327 A CN102850327 A CN 102850327A
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- 0 *C(c1ccc(*)cc1)=NC(*)=O Chemical compound *C(c1ccc(*)cc1)=NC(*)=O 0.000 description 6
- DXUTWLTWGKEWJA-UHFFFAOYSA-N CCOC(CC(COCc1ccccc1)=O)=O Chemical compound CCOC(CC(COCc1ccccc1)=O)=O DXUTWLTWGKEWJA-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to a technical field of a method for preparing Dabigatran etexilate. The invention provides a novel intermediate compound represented by the formula 7. With the intermediate, the target compound Dabigatran etexilate can be obtained with high yield with a one-step reaction. Compared with prior arts, reagents adopted by the Dabigatran etexilate preparation method provided by the invention are cheap; the reaction time in each step is short, a yield is high, conditions are mild, and intermediate purification is convenient. The method is an excellent high-yield low-cost method for preparing Dabigatran etexilate.
Description
Technical field
The invention belongs to the chemical synthesis process technical field of oral anticoagulant dabigatran etcxilate.
Background technology
Dabigatran etcxilate (Dabigatran etexilate) is the new oral anticoagulation medicine of German Boehringer Ingelheim company exploitation.In April, 2008, at first in Germany and Britain's listing, commodity are called Pradaxa, and its chemical structure is as follows:
Boehringer Ingelheim company has reported article one synthetic route in patent WO9837075, its synthetic method is as follows:
This synthetic route is linear synthetic, and yield is low, intermediate and end product separation and purification difficulty, and also the step of synthetic amidino groups uses a large amount of hydrochloric acid gases, and seriously polluted, serious to equipment corrosion;
2006, Boehringer Ingelheim company has reported again another synthetic route of dabigatran etcxilate, and was as follows:
This synthetic route total recovery is not high.The benzoglyoxaline ring building-up process in the condensing agent that uses carbonyl dimidazoles, pivaloyl chloride, propane phosphoric anhydride are arranged, wherein carbonyl dimidazoles and propane phosphoric anhydride price, the pivaloyl chloride foul smelling all is not suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of new intermediate compound for preparing dabigatran etcxilate and preparation method thereof.
Another object of the present invention is to solve the deficiency of the synthetic dabigatran etcxilate of above-mentioned route, the method for the low-cost synthetic dabigatran etcxilate of a kind of high yield is provided.
In order to achieve the above object, the technical solution adopted in the present invention is as follows:
As shown in the formula compound 7:
Wherein R represents alkyl or aryl.
The preparation method of above-claimed cpd 7, it comprises the steps:
(1) formula 2 compounds and formula 3 compounds catalyzed reaction in solvent obtain formula 4 compounds:
(2) formula 4 compounds and SULPHURYL CHLORIDE reaction preparation formula 7 compounds.
Wherein R represents alkyl or aryl.
Used solvent comprises alcohols in the above-mentioned step (1), alkane, aromatic hydrocarbons, ester class, ethers etc.Be preferably alcohols, be selected from ethanol, methyl alcohol, Virahol.Used catalyzer comprises road protonic acid and Lewis acid, comprises protonic acid, Lewis acid and ammonium salt, such as methylsulfonic acid, tosic acid, tindichloride, tin tetrachloride, brometo de amonio, ammonium chloride etc.The temperature of reaction is 25 ℃ and arrives the reflux temperature that uses solvent, generally at 25-100 ℃.
In the above-mentioned step (2), R represents alkyl or aryl; The alkyl of the preferred 1-10 of a said alkyl carbon atom, most preferable or ethyl, the preferred phenyl of said aryl, p-methylphenyl, p-nitrophenyl etc., most preferably phenyl or p-methylphenyl.
Another preparation method of compound 7, it comprises the steps:
(1) catalyzed reaction in solvent obtains formula 6 compounds with formula 2 compounds and formula 5 compounds, and formula 6 compound for catalysis hydrogenations remove benzyl and get formula 4 compounds:
(2) formula 4 compounds and SULPHURYL CHLORIDE reaction preparation formula 7 compounds
Wherein R represents alkyl or aryl.
Another preparation method of above-mentioned compound 7, step (1) obtains the reaction of formula 6 compounds, and used catalyzer comprises protonic acid, Lewis acid and ammonium salt, such as methylsulfonic acid, tosic acid, tindichloride, tin tetrachloride, brometo de amonio, ammonium chloride etc.Used solvent comprises alcohols, alkane, aromatic hydrocarbons, ester class and ethers; Be preferably alcohols, such as ethanol, methyl alcohol or Virahol etc.Temperature of reaction is 25 ℃ and arrives the reflux temperature that uses solvent, generally at 25-100 ℃.By the reaction of formula 6 preparation formulas 4, directly in the reaction solution of preparation formula 6, directly add palladium carbon catalyst, logical hydrogen is deviate from benzyl and is obtained.
Another preparation method of above-mentioned compound 7, in the above-mentioned step (2), R represents alkyl or aryl; The alkyl of the preferred 1-10 of a said alkyl carbon atom, most preferable or ethyl, the preferred phenyl of said aryl, p-methylphenyl, p-nitrophenyl etc., most preferably phenyl or p-methylphenyl.
Formula 7 compounds are as the application of the new intermediate of preparation dabigatran etcxilate.Its concrete grammar comprises the steps:
(1) under alkaline condition, formula 7 compounds and formula 8 compound condensations obtain formula 1 compound:
Wherein R represents alkyl or aryl; Hex represents n-hexyl.
The alkyl of the preferred 1-10 of the R carbon atom in said formula 7 compounds, most preferable or ethyl, the preferred phenyl of said aryl, p-methylphenyl, p-nitrophenyl etc., most preferably phenyl or p-methylphenyl.The alkali that uses comprises organic bases and mineral alkali, and organic bases is selected from triethylamine, diisopropyl ethyl amine or pyridine etc.; Mineral alkali is selected from salt of wormwood, yellow soda ash, saleratus or sodium bicarbonate.
Beneficial effect of the present invention: patent of the present invention provides a kind of new midbody compound 7, and that utilizes that this intermediate single step reaction just can high yield obtains the target compound dabigatran etcxilate.Compared with prior art, the reagent low price that the preparation method of the dabigatran etcxilate that patent of the present invention provides adopts, it is short that each goes on foot the reaction times, yield is high, mild condition, purification of intermediate is convenient, is undoubtedly the excellent process of the low-cost preparation of a kind of high yield dabigatran etcxilate.
Embodiment
Embodiment 1: the preparation of formula 4 compounds
With formula 2 compounds (5.0g, 0.0146mol), formula 5 compound (3.8g; 0.0161mol), ammonium chloride 0.5g, 30ml dehydrated alcohol are incubated 65-70 ℃ of stirring reaction 3h under nitrogen protection; adding 1.0g content in this reaction solution is 5% palladium carbon catalyst, logical hydrogen return stirring reaction, and TLC monitors to raw material reaction complete; remove by filter catalyzer and inorganic salt; be concentrated into driedly, add ethyl acetate 20ml and stir, filter and separate out solid; dry to get the 5.0g target product, productive rate 89.6%.
Embodiment 2: the preparation of formula 4 compounds
With formula 3 compound 4.3g(0.0292mol), formula 2 compound 5.0g(0.0146mol) 0.5g ammonium chloride; ethanol 30ml is heated to 65-70 ℃ of stirring reaction two hours under nitrogen protection, steaming desolventizes, and adds methylene dichloride 100ml; water 100ml * 2 washings; anhydrous sodium sulfate drying filters evaporate to dryness, adds ethyl acetate 30ml; solid is separated out in stirring; filter, dry to get the 4.8g product, productive rate 86.0%.
Fusing point: 140-143 ℃.ESI-MS(m/z):383[M+H]
+
Embodiment 3: the preparation of formula 7 compounds, R is methyl
Formula 4 compounds (5.0g, 0.0131mol), triethylamine (3.3g, 0.0327mol) are added in the 100ml methylene dichloride, 5-10 ℃ drips methylsulfonyl chloride (3.0g in 2min, 0.0262mol), stirring reaction 2min adds the 100ml frozen water, 2ml ammoniacal liquor, stir 5min, separatory, organic layer washs with saturated 100ml sodium bicarbonate, the washing of 100ml saturated sodium-chloride, organic layer are steamed to desolventize and are directly carried out alkylated reaction.
ESI-MS(m/z):461[M+H]
+
Embodiment 4: the preparation of formula 8 compound hydrochlorides
With p-Aminobenzamidine dihydrochloride 42g, 0.2mol) three mouthfuls of reaction flasks of adding 1000mL, add 500mL acetone, in 0-5 ℃ of sodium hydroxide solution that drips 160mL 4mol/L, stir 30min, must clarify system, drip the just own ester of chloroformic acid (33g, 0.2mol), 5-10 ℃ of stirring reaction 30min of control temperature, separatory, after upper strata acetone is concentrated, add ethyl acetate 300mL, separatory, organic layer is washed 1 time with 200mL, 200mL saturated common salt water washing 1 time, anhydrous Na SO4 is dry, is concentrated into dried, add 200mL ethanol and stir the saturated acidic alcohol of the lower 50mL of dropping, separate out white solid, be incubated 5-10 ℃ of 1h, filter, filter cake washs rear 50 ℃ of decompression dryings with ethyl acetate 100mL and gets white powder solid 55g, productive rate 92%.
Embodiment 5: the preparation of dabigatran etcxilate
Formula 8 hydrochloride (4.0g, 0.0133mol) adding 100ml single port flask, the sodium hydroxide solution that adds 20ml 10%, the 90ml butylacetate adds 50 ℃ and stirs 30min, separatory, water layer extracts once with butylacetate 10ml, merge organic layer, with the washing of 50ml saturated sodium bicarbonate once, the water washing of 100ml saturated common salt once.Organic layer changes the 250ml there-necked flask over to, adds the formula 7 compound oily matter of embodiment 5 systems, sodium iodide 0.5g, Tetrabutyl amonium bromide 0.5g, water 15ml, sodium bicarbonate (2.2g, 0.0262mol) 40 ℃ of stirring reaction 2h, be warming up to again 70 ℃ of stirring reaction 2h, be cooled to room temperature, filter, the washing of 20ml butylacetate, the 50ml washing is dried to get dabigatran etcxilate 6.9g, productive rate 84%.
The preferred specific embodiment of the present invention has more than been described.The technician of the industry should understand, and the present invention is not restricted to the described embodiments, and the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the scope of protection of present invention.The claimed scope of the present invention defining by appending claims and equivalent thereof.
Claims (24)
- As shown in the formula compound 7:
Wherein R represents alkyl or aryl. - 2. compound 7 as claimed in claim 1, it is characterized in that: R is the alkyl of 1-10 carbon atom.
- 3. compound 7 as claimed in claim 2, it is characterized in that: R is methyl or ethyl.
- 4. compound 7 as claimed in claim 1, it is characterized in that: R is phenyl, p-methylphenyl or p-nitrophenyl.
- 5. compound 7 as claimed in claim 4, it is characterized in that: R is phenyl or p-methylphenyl.
- 6. the preparation method of the described any compound 7 of claim 1-5, it comprises the steps:(1) formula 2 compounds and formula 3 compounds catalyzed reaction in solvent obtain formula 4 compounds:
(2) formula 4 compounds and SULPHURYL CHLORIDE reaction preparation formula 7 compounds.
Wherein R represents alkyl or aryl. - 7. the preparation method of compound 7 as claimed in claim 6, it is characterized in that: the used solvent of step (1) comprises ethanol, methyl alcohol and Virahol.
- 8. the preparation method of compound 7 as claimed in claim 6, it is characterized in that: the used catalyzer of step (1) is protonic acid, Lewis acid or ammonium salt.
- 9. the preparation method of compound 7 as claimed in claim 8, it is characterized in that: the used catalyzer of step (1) is methylsulfonic acid, tosic acid, tindichloride, tin tetrachloride, brometo de amonio or ammonium chloride.
- 10. the preparation method of compound 7 as claimed in claim 6 is characterized in that: the temperature of reaction of step (1) be 25 ℃ to the reflux temperatures that use solvent.
- 11. the preparation method of compound 7 as claimed in claim 6 is characterized in that: R is the alkyl of 1-10 carbon atom in the step (2).
- 12. the preparation method of compound 7 as claimed in claim 11 is characterized in that: R is methyl or ethyl in the step (2).
- 13. the preparation method of compound 7 as claimed in claim 6 is characterized in that: R is phenyl, p-methylphenyl or p-nitrophenyl in the step (2).
- 14. the preparation method of the described any compound 7 of claim 1-5, it comprises the steps:(1) catalyzed reaction in solvent obtains formula 6 compounds with formula 2 compounds and formula 5 compounds, and formula 6 compound for catalysis hydrogenations remove benzyl and get formula 4 compounds:
(2) formula 4 compounds and SULPHURYL CHLORIDE reaction preparation formula 7 compounds
Wherein R represents alkyl or aryl. - 15. the preparation method of compound 7 as claimed in claim 14 is characterized in that: step (1) obtains the reaction of formula 6 compounds, and used catalyzer is protonic acid, Lewis acid or ammonium salt.
- 16. the preparation method of compound 7 as claimed in claim 15 is characterized in that: step (1) obtains the reaction of formula 6 compounds, and used catalyzer is methylsulfonic acid, tosic acid, tindichloride, tin tetrachloride, brometo de amonio or ammonium chloride.
- 17. the preparation method of compound 7 as claimed in claim 14 is characterized in that: step (1) obtains the reaction of formula 6 compounds, and temperature of reaction is 25 ℃ and arrives the reflux temperature that uses solvent.
- 18. the preparation method of compound 7 as claimed in claim 14 is characterized in that: step (1) in the reaction solution of preparation formula 6, directly adds palladium carbon catalyst by the reaction of formula 6 preparation formulas 4, and logical hydrogen is deviate from benzyl and obtained.
- 19. the preparation method of compound 7 as claimed in claim 14 is characterized in that: in the step (2), R is the alkyl of 1-10 carbon atom.
- 20. the preparation method of compound 7 as claimed in claim 19 is characterized in that: in the step (2), R is methyl or ethyl.
- 21. the preparation method of compound 7 as claimed in claim 14 is characterized in that: in the step (2), said aryl R is phenyl, p-methylphenyl or p-nitrophenyl.
- 22. described any formula 7 compounds of claim 1-5 are used for preparing dabigatran etcxilate.
- 23. formula 7 compounds as claimed in claim 22 prepare the method for dabigatran etcxilate, it is characterized in that: under alkaline condition, formula 7 compounds and the reaction of formula 8 compound condensations obtain formula 1 compound:Wherein Hex represents n-hexyl.
- 24. formula 7 compounds as claimed in claim 23 prepare the method for dabigatran etcxilate, it is characterized in that: the alkali that uses is selected from triethylamine, diisopropyl ethyl amine or pyridine etc. as machine alkali or mineral alkali, organic bases; Mineral alkali is selected from salt of wormwood, yellow soda ash, saleratus or sodium bicarbonate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160060248A1 (en) * | 2013-03-25 | 2016-03-03 | Usv Limited | Synthesis of dabigatran |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101346360A (en) * | 2005-12-21 | 2009-01-14 | 贝林格尔.英格海姆国际有限公司 | Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof |
| WO2011061080A1 (en) * | 2009-11-18 | 2011-05-26 | Boehringer Ingelheim International Gmbh | Method for producing dabigatran etexilate |
-
2012
- 2012-06-19 CN CN201210203997.1A patent/CN102850327B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101346360A (en) * | 2005-12-21 | 2009-01-14 | 贝林格尔.英格海姆国际有限公司 | Improved process for the preparation of 4-(benzimidazolylmethylamino)-benzamides and the salts thereof |
| WO2011061080A1 (en) * | 2009-11-18 | 2011-05-26 | Boehringer Ingelheim International Gmbh | Method for producing dabigatran etexilate |
Non-Patent Citations (1)
| Title |
|---|
| 邢松松等: "达比加群酯的合成", 《中国医药工业杂志》, vol. 41, no. 5, 31 December 2010 (2010-12-31) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160060248A1 (en) * | 2013-03-25 | 2016-03-03 | Usv Limited | Synthesis of dabigatran |
| US9688657B2 (en) * | 2013-03-25 | 2017-06-27 | Usv Private Limited | Synthesis of dabigatran |
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Effective date of registration: 20181227 Address after: 037300 First Pharmaceutical Park, Datong Economic and Technological Development Zone, Shanxi Patentee after: Weiqida Pharmaceutical Co., Ltd. of China National Pharmaceutical Industry Corporation Ltd. Address before: 200137, Shanghai, Pudong New Area built 378 land Co-patentee before: Shanghai Shyndec Pharmaceutical Co., Ltd Patentee before: Shanghai Modern Pharmaceutical Co., Ltd. |
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